Abstract/Project Summary Most human spinal cord injuries (SCIs) are anatomically incomplete, with spared axons spanning the damaged spinal segments. However, about a half of these patients have a total loss of muscle control and sensation below the injury level. An important but under-studied question is why such spared connections fail to mediate functional recovery in these cases. Recent advances in human studies show that epidural stimulation combined with rehabilitative training allows some chronically paralyzed patients with SCI to regain voluntary movement, highlights the feasibility of reactivating such dormant spinal circuitry. However, the limited functional recovery only occurs when the stimulation is on. Thus, understanding why this spared spinal circuitry is dysfunctional after SCI, and how it can best be reactivated, should provide key insights into developing novel functional restoration strategies for SCI. In mice with staggered bilateral hemisections, in which the lumbar spinal cord is deprived of all direct brain-derived innervation but dormant relay circuits remain between the damaged segments, we discovered that systematic treatment with a KCC2 agonist, or over-expression of KCC2, is able to restore stepping ability in these paralyzed mice. We showed that such manipulations are able to correct over-inhibition within the spinal relay zone, allowing this detour circuit to transmit the brain-derived commands to the hindlimb motor command center in the lumbar spinal cord, leading to functional recovery. With these exciting preliminary results, this proposed study will address several related questions: what is the mechanism underlying injury-induced KCC2 down-regulation in injured spinal cord? Why the achieved functional recovery is partial and how to further enhance such functional recovery? What are the effects of these circuit-modifying treatments in more clinically relevant injury models, namely severe contusion models?